19-substituted-20-keto-10alpha-pregnenes



United States Patent 3,249,602 19-SUBSTITUTED-20-KETO-10ot-PREGNENES Alexander D. Cross, Mexico City, Mexico, assignor to Syntex Corporation, Panama, Panama, a'corporation of Panama No Drawing. Filed June 15, 1964, Ser. No. 375,384

22 Claims. (Cl. 260-23155) The present invention relates to novel cyclopentano- CH2-O R l OH "Ice In the above formulae, R represents hydroxyl, tosyloxy, a hydrocarbon car-boxylic acyloxy group of less than 12 carbon atoms or a cyano group; R represents hydroxyl, a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms or a cyano group; R may be hydrogen; R and R taken together, and R and R taken together, represent an oxo group or a methylene grouping; R represents hydrogen or a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R represents hydrogen, hydroxyl or a hydrocarbon car-boxylic acyloxy group of less than 12 carbon atoms; R represents hydrogen; T represents hydrogen or methyl; R and T taken together and OR and T taken together, represent a 1604,175- l-ower alkylidene-dioxy grouping; 5 indicates that the substituent attached thereby to the steroid nucleus may have the 0a or 18 configuration; X represents a halogen atom having an atomic weight of less than Y may be hydrogen or a halogen atom having an atomic weight of less-than 125; and Z may be a fl-hydroxyl group or an oxo group.

The acyl and aeyloxy groups are derived from hydro carbon carboxylic acids containing less than 12 carbon atom-s which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate, and 13- chloropropionate.

The compounds represented by Formulae A, B, C and D are powerful progestational agents with good oral activity. In addition, they have anti-androgenic, antigonadotropic and anti-estrogenic properties and are very useful in fertility control. Furthermore, they may be used inthe treatment of premenstrual tens-ion and exhibit blood chlosterol lowering and diuretic activities. When applied topically, these compounds are very useful in the treatment of acne.

The compounds represented by Formulae E and F are valuable cortical hormones with high anti-inflammatory, 'low catabol-ic, glycogenic and thymol-ytic activities. In

, addition, they are anti-androgenic, anti-gonadotropic and anti-estrogenic hormones. Furthermore, they have topical activity in skin disorders such as psoriasis, allergic dermatitis and the like. 4

The novel compounds of the present invention are prepared by the process exemplified as follows:

In the above formulae, R, R R R R R X and Y have the same meaning as set forth hereinbefore; R represents hydrogen or a tetrahydropyranyloxy grouping;

and R and T together have the same meaning as R and T together.

In accordance with the above equation, the starting 35 tetrahydropyranyloxy 20 cycloethylenedioXy-19- nor-A -pregnen 6 x-ol(I) is treated with a lower alkyl vinyl ether e.g. ethyl vinyl ether, in the presence of a catalytic amount of a mercuric salt of a weak acid, such as mercuric acetate, for a period of time of the order of hours, preferably at reflux temperature, to give the corresponding 6a-vinyloxy compound (II), which upon refluxing in a high boiling point solvent, e. g., Decalin, [for about 4 hours, furnishes the corresponding Bfl-tetrahydropyranyloxy-20-cyclo ethylenedioxy l9 formyl-A lOu-pregnene derivative (III). The latter compound is conventionally reduced, as for example, with sodium boro hydride, to give the corresponding 19-hydroxymethyl- A -10a-pregnene (IV) which upon reaction with tosyl chloride in pyridine at 0 C. for about 24 hours, yields the corresponding 19 tosyloXymethyl-A -1Om-pregnene (V). The latter compound is treated with an alkali X "R5 (5H MNT a onion:

=0 X on 011 Cg, YMNT QB j XVI (anion: i X on om \/\i: on, NWT

metal halide such as potassium fluoride, lithium chloride or lithium bromide, or an alkali metal cyanide, such as potassium cyanide, in a suitable solvent, for exa-mple, :dimethyl formamide or acetonitrile, at reflux temperature for about 5 hours to give, respectively, the corresponding 19-cyanomethyl-A -loot-pregnene (VI), or the corresponding 19- cyanomethyl-A -1Oa-pIegnene (VII).

The 19-formyl compound (III) upon treatment with triphenyl phosphonium methyl bromide in the presence of a lower alkyl lithium, e.g., 'butyl lithium, in an inert solvent, such as ether, for about '14 hours, affords the corresponding 19 vinyl A 10a pregnene compound (VIII).

The compounds obtained by the methods described hereinbefore having a tetrahydropyranyloxy group at C- 3 and/or C-l7 and a cycloethylenedioxy grouping at C2() (III, IV, V, VI, VII and VIII), are conventionally hydrolyzed in a weak acid medium to give the corresponding 20-keto-3/3-hydroxy and/ or 1'7u-hydroxy-A IOu-pregnenes (IX and XIV), which upon treatment with a lower a'lkanone, such as cyclohex'anone, in the presence of an aluminum lower'alkoxide, e.g., aluminum isopropoxide, in an inert solvent, for example toluene,

7 at reflux temperature for approximately 15 minutes afford the corresponding A -lu-pregnene-3,20-dione compound-s (X and XV). having a 17u-hydroxyl or a 16a,17u-alkylidenedioxy grouping, with the exception of the 19-tosyloxy-methyl derivatives, upon treatment with iodine in the presence of'calcium oxide gives the corresponding 2l-iodo derivative, which is reacted with potassium acetate, in a suitable solvent, such as acetone, preferably at reflux temperature, thus affording the corresponding 21-acetoxy derivative, which, in turn, upon incubation with adrenal glands in a suitable medium, e.g. an aqueous solution of alkali metal phosphates and chlorides and in magnesium sulfate, mixed with an aqueous solution Olf furnaric acid and sodium hydroxide for a period of time of the order of 3 hours, at approximately 28-37 0., yields the corresponding 19-substituted A -l0 -pregnenell 8, 2l-diol-3,20-dione (XI and XVI). The primary hydroxyl groups of the latter compound are protected by conventional conversion to the corresponding acyloxy derivative,.which upon treatment with mesyl chloride in dimethyl formamide and pyridine at approximately 80 C., for about 30 minutes, produces the corresponding 19-substituted-A D-10a-pregnadien 21-ol-3,20-dione primary alcohol acylate. The latter derivative is treated with an N-bromoa-mide or imide, such as N- bromoacetamide, in the presence of perchloric acid, in an inert solvent, such as for example dioxane to give the corresponding A -9a-bromo-11fi-ol which upon treatment with a mild 'base, such as potassium acetate, in a suitable solvent, e.g., acetone, preferably at reflux temperature, afford the corresponding l9-substituted-9B,ll,8- oxido-A -10u-pregnen-Z1-ol-3,20dione primary alcohol acylate. The latter 9/3,11[3-oxido compound, upon treatment with a hydrogen halide, such as hydrogen fluoride or hydrogen chloride, in a suitable inert organic solvent, e.g., methylene chloride'or chloroform, yields the corresponding 19 substituted 9ot-halo-A -l0a-pregnenel1B, 21-diol-3,20-'dione primary alcohol acylate (XII and XVII; Y=halogen). The 11,8-hydroxyl group of the latter compound and of the corresponding 9a-unsubstituted-llfl-hydroxy compound (XI and XVI) is'oxidized conventionally, e.g., with Jones reagent (chromium trioxide in sulfuric acid-Water) thus afiording the corresponding ll-ketone (XIII and XVIII). Y

The compounds of the present invention having a 21- acyloxy group, may be saponified by conventional treatment with a base to produce the corresponding 21-free alcohols which, in turn, may be acylated conventionally in pyridine with an acylating agent to .give the corresponding 21-acylates, wherein the acyl group may be difierent from the previously saponified one.

The compounds of the present invention having a primary and/or a Sfi-hydroxyl group, are conventionally acylated in pyridine with an acylating agent, such as an anhydride or a chloride of a hydrocarbon carboxylic acid of the type described hereinbefore, to give the corresponding acylates.

The compounds of the present invention having in the molecule a primary and/or a 35- and/or or tertiary hydroxyl group, (e.g. at C-l7), are conventionally esterified in the presence of p-toluenesulfonic acid with an acylating agent, such as acetic anhydride, caproic anhydride, cyclopentylpropionic anhydride, or enanthic anhydride, to produce the corresponding esters.

The following specific examples serve to illustrate but are not intended to limit the scope of the present invention.

PREPARATION 1 To a solution of 4 g. of the 3-acetate of A -pregnene- 35,19-di0l-20-one in 150 cc. of dry benzene, were added 6 g. of lead tetraacetate and 8 g. of calcium carbonate and the mixture was refluxed for 2 hours. It was cooled, filtered, water was added to the filtrate, the benzene layer Any of the latter compounds was separated, washed with water and the benzene was evaporated under reduced pressure; upon chromatography of the residue on neutral alumina, there was obtained the diacetate of 19-nor-A -pregnene-3[3,6/3-diol-20-one.

A mixture of 2 g. of the diacetate of 19-nor-A pregnene-35,6,B-diol-20-one, 25 cc. of dry benzene, 10 cc. of ethylene glycol and 50 mg. of p-to luenesulfonic acid monohydrate was refluxedfor 16 hours using a water separator. It was then washed with a sodium bicarbonate solution, water and subsequently dried and evaporated to dryness. Recrystallization from acetone-hexane yielded the diacetate of 20-cycloethylenedioxy-l9-nor-A -pregnene-3/3,6 8-di-ol.

A solution of 0.17 g. of potassium hydroxide in 0.2 cc. of water and 2.5 cc. of methanol was added over 30 minutes to a boiling solution of 1.5 g. of the latter compound in 30 cc. of methanol. Boiling was continued for a further 2 hours and the solution was then cooled, neutralized with acetic acid and concentrated under reduced pressure. Addition of water, followed by crystallization of the precipitated solid frornacetone-hexane, produced 20- cycloethylenedioxy-19-nor-A -pregnene-3fi,6B-diol.

A mixture of 1.2 g. of the latter steroid in 20 cc. of dioxane, and 1.1. molar equivalents of 2,3-dichloro-5,6- dicyano-l,4-benzoquinone was kept at room temperature for 3 hours. tion was filtered 0115, and the filtrate evaporated to dryness. The residue was dissolved in acetone and filtered through 20 g. of alumina. Crystallization from acetone-hexane gave ZO-cycloethylenedioxy-19-nor-A -pregnen-3fi-ol-6- one.

2 cc. of dihydropyrane were added to a solution of l g. of the latter steroid in 15cc. of benzene and about 1 cc. was distilled to remove moisture. 0.4 g. of p-toluenesulfonic acid were added to the cooled solution, which was then allowed to stand at room temperature for 24 hours. The solution was washed with sodium carbonate and water, dried and evaporated. The residue was chromatographed on 15 g. of neutral alumina. Crystallization of the fractions eluted with hexane from pentane yielded 36 tetrahydropyranyloxy-ZO-cycloethylenedioxy- 19-nor-A -pregnen-6-one.

A solution of 0.5 g. of the latter steroid in 50 cc. of tetrahydrofuran was added over a 30 minute period to a stirred suspension of l g. of lithium aluminum hydride in 50 cc. of anhydrous tetrahydrofuran. The ,mixture was refluxed for 2 hours, then cooled and cautiously treatedwith 5 cc. of ethyl acetate and 2 cc. of water. Solid sodium sulfate was added, the inorganic material filtered off and thoroughly washed with hot ethyl acetate, the combined organic solutions upon evaporation yielded a crude material which was chromatographed on alumina to give 3fi-tetrahydropyranyloxy-ZO-cycloethylenedioxyl9-nor-A -pregnen-6a-ol.

The starting compounds listed under I were treated by the same sequence of reactions thus giving the corresponding final products set forth under II.

The hydroquinone formed during the reac- B-aeetate 0i IGa-methyl-A -pIegmane-319, 19-di01-20-one.

B-acetate of lfi S-methyl-n -pregnene'3fl, 19-diol-20-one.

S-acetate of 16a. 17a-isopropy1idenedioxy-M-pregnene-BB, 19- diol-ZO-one.

3,17-diacetate of A -pregnene-3B,

1704,19-t1l0l-2001'16.

3,17-diacetate of lfia-methyl-N- pregnene-3fl,17a,19-triol-20-0ne.

Example I A mixture of 5 g. of 3B-tetrahydropyranyloxy-ZO-cycloethylenedioxy-19-nor-A -pregnen-6a-ol, 3 g. of freshly crystallized mercuric acetate and 100 cc. of purified ethyl vinyl ether was refluxed for 10 hours. The resulting mixture was cooled, washed with cold aqueous sodium carbonate solution, dried and concentrated to a small volume. The concentrate was chromatographed on alumina, thus giving SB-tetrahydropyranyloxy-20-cycloethylenedioxy-6avinyloxy-l9-nor-A -pregnene (Compound No. 1).

' The compounds listed hereinafter under I were treated by the same procedure, thus giving the corresponding products set forth under II.

I Cpd.

3B-tetrahydropyranyloxy-20 cycloethylenedioxy-6avinyloxy'lfia-methyl-lilnor-A -pregnene.

3B-tetrahydropyranyloxy-ZO- cycloethylenedioxy-6avinyloxy-IGB-methyl-lQ- nor-A -pregnene.

3B-tetrahydropyranyloxy-20- eyclocthylenedioxy6avinylxy-16a,17a-ls0propylidenedioxy-l9-n0r-A pregnene.

36,17a-bis-tetrahydropyranyL oxy-20-cycloethylenedioxytioz-vinyloxy-lQ-nor-A pregnene.

3B,17a-bistetrahydropyranyloxy-ZO-cyeloethylenedioxyfia-vinyloxy-lfia-methyl-IQ- nor-A -pregnene.

3Btetrahydropyranyloxy-ZO- cycloethylenedioxy-16amethyl-19-nor-A -pregnen- Gar-O1.

3fl-tetrahydropyranyloxyatl 3 cycloethylenedioxy-166- rnetnyl-lQ-nor-A -pregnen- Bfl-tetrahydropyranyloxy-2t 4 cycloethylenedioxydfia,17aisopropylidenedioxy-lQ-nor- A -preguen-6a-ol.

3B,17a-bistetrahydropyranyl- 5 oxy--cycloethylenedioxy- 19-nor-A -pregnen-fia-ol.

313,17 a-bis-tetrahydropyranyl- 6 oxy-20-cycloethylenedioxylfia-methyLlQ-nor-M pregnen-fia-ol.

Example I] A mixture of 1 g. of compound No. 1 and 10 cc. of Decalin was refluxed, under nitrogen, for 4 hours, then it was evaporated to dryness under reduced pressure. The resulting residue was crystallized from acetonehexane, thus giving 3B-tetrahydropyranyloxy 20 cycloethylenedioxy-19-formyl-A -10a-pregnene (Cpd. No. 7).

The compounds Nos. 2 to 6, inclusive, were treated by the above procedure thus giving respectively.

Example 1 11 A solution of 1 g. of sodium borohydride in 3 cc. of water was added to an ice-cooled solution of l g. of compound No. 7 in 120 cc. of methanol and the mixture was allowed to stand for 16'h0urs at room temperature. The excess reagent was decomposed by addition of acetic acid, the solution concentrated to small volume in vacuo and diluted with water. The product was extracted with ethyl acetate, the extract was washed with water, dried and evaporated. The solid residue was purified by crystallization from acetone-hexane to give 3B-tetrahydropyranyloxy 20 cycloethylenedioxy 19 hydroxymethyl-A -10a-p regnene (Cpd. No. 13).

The compounds Nos. 8 to 12, inclusive, were treated by the latter procedure, thus aflfording respectively.

Cpd. No.:

14. 3 B tetrahydropyranyloxy 20 cycloethylenedioxy 19 hydroxymethyl 16oz -.methyl A -10upregnene 15. 35 tetrahydropyranyloxy 20 cycloethylenedioxy 19 hydroxymethyl 16,8 methyl A -10ozpregnene 16. 3,8 tetrahydropyranyloxy 20 cycloethylenedioxy 19 hydroxymethyl 1611,1704 isopropylidenedioxy-A -10a-pregnene 17. 3,8,17a bis tetrahydropyranyloxy 20 cycloethylenedioxy 19 hydroxymethyl A 10apregnene 18. 3 8,17 bis tetrahydropyranyloxy 20 cycloethylenedioxy 19 hydroxymethyl 16a methyl- A -10u-pregnene Example IV A solution of 1 g. of compound No. 13 in 5 cc. of pyridine was treated with 0.5 g, of tosyl chloride and kept at 0 C. for 24 hours, it was then diluted with water and the precipitate separated by filtration, thus giving 35- tetrahydropyranyloxy 20 cycloethylenedioxy 19-tosyloxymethyl-A -IOa-pregnene (Cpd. No. 19).

The compounds Nos. 14 to 18, inclusive, were treated by the same procedure, thus yielding respectively.

Example V A suspension of 10 g. of potassium fluoride in 50 cc. of dimethyl formamide was heated to boiling and then a solution of 2 g. of compound No. 19 in 10 cc. of di methyl formamide was added. The mixture was refluxed for 5 hours, cooled and poured into water. The formed precipitate was filtered off and crystallized to give 3,8- tetrahydropyranyloxy 20 cycloethylenedioxy- 19-fluoromethyl-A -10a-pregnene (Cpd. No. 25).

The compounds Nos. 20 to 24, inclusive, were treated by the same procedure, thus affording respectively:

Cpd. No.:

26. 3fi-tetrahydropyranyloxy-20-cycloethylenedioxy- 19-fluoromethyl-16a-methyl-A IOa-pregnene 27. 3 fi-tetrahydropyranyloxy-ZO-cycloethylenedioxyl9-fluoromethyl-165-methyl-A -lOa-pregnene 28. 3,B-tetrahydropyranyloxy-ZO-cycloethylenedioxy- 19-fluoromethyl-16a,17a-isopropylidenedioxy- A -10a-pregnene 29. 3B,17a-bis-tetrahydropyranyloxy-20 cycloethylenedioxy-19-fiuoromethyl-A -1Oa-pregnene 3 0. 3p ,17a-bis-tetrahydropyranyloxy-ZO-cycloethylenedioxy-19-fiuoromethyl-16a-methyl-A IOaregnene Example VI The starting compounds of Example V were treated following exactly the procedure set forth in that example,

l 1 except that potassium fluoride was substituted by lithium chloride, thus giving respectively:

Cpd. No.:

3 1. 3 fi-tetrahydropyranyloxy-20-cycloethylenedioxy- 19-chloromethy1-A -lOu-pregnene 32. 3 B-tetrahydropyranyloxy-ZO-cycloethylenedioxy- 19-chlor0methyl-16oc-methyl-A -lOa-pregnene 33. 35-tetrahydropyranyloxy-20-cycloethylenedioxy- 19-chloromethyl-16,8-methyl-A -10a-pregnene 34. 3,8-tetrahydropyranyloxy-ZO-cycloethylenedioxy- 19-chloromethyl-l6a,l7a-isopropylidenedioxy- A -la-pregnene 3 5. 3 {3, l7zx-bis-tetrahydropyranyloxy-20-cycloethylenedioxy-l9-chloromethyl-A -IOa-pregnene 3 6. 3B,17wbis-tetrahydropyranyloxy-20-cycloethylenedioxy-19-chloromethyl-16a-methyl-A a-pregnene Example VII The starting compounds of Example V were treated in accordance with said example except that lithium bromide was used instead of potassium fluoride, thus furnishing respectively:

Cpd. No.:

37. 3,8-tetrahydropyranyloxy-20-cycloethylenedioxy- 19-bromomethyl-A -1Oaregnene 3 8. 3 fl-tetrahydropyranyloxy-20-cycloethylenedioxy- 19-bromomethyl-16a methyl-A -lOa-pregnene 39. 3[3-tetrahydropyranyloxy-ZO-cycloethylenedioxy- 19-brornomethyl-16,8-methyl-A -10a-pregnene 40. 3 ,G-tetrahydropyranyloxy-ZO-cycloethylenedioxyl9-bromomethyl-16a,17a-isopropylidenedioxy- AP-lOa-pregnene 41. 3 L3, 17a-bis-tetrahydropyranyloxy 20-cycloethylenedioxy-l9-bromomethyl-A :10oc-pregnene 42. 3 ,8,17a-bis-tetrahydropyranyloxy-ZO-cycloethylenedioxy-l9-bromomethyl-16x-methyl-A IOa-pregnene Example VIII The starting compounds of Example V were treated following the procedure described in said example, except that potassium fluoride was substituted by potassium cyanide and 'acetonitrile was used instead of dimethyl formamide thus giving respectively:

A suspension of 14.5 g. of triphenylphosphonium methyl bromide in 250 cc. of anhydrous ether was treated, under an atmosphere of nitrogen, with 40 cc. of 1 N ethereal solution of butyl lithium and the mixture was stirred for 2 hours at room temperature. A solution of 5 g. of compound No. 7 in 100 cc. of ether was then added dropwise in the course of minutes and with stirring. The reaction mixture was stirred for 6 hours further and let stand at room temperature overnight. The ether was displaced with dry tetrahydrofuran by distillation and then refluxed for 8 hours. It was then cooled,

' diluted with water and extracted several times with ethyl acetate, the organic extract was washed with water, dried 12 over anhydrous sodium sulfate and evaporated to dryness. Chromatography of the residue and recrystallization of the solid eluates from acetone-hexane gave 3fi-tetrahydropyranyloxy 20 cycloethylenedioxy l9 vinyl A lOa-pregnehe (Cpd. N0. 49).

The compounds Nos. 8 to 12, inclusive, Weretreated exactly by the same method, to give respectively:

Cpd. No.:

v 50. 3,B-tetrahydropyranyloxy-ZO-cycloethylenedioxy- 19-viny1-16u-methy1-A5-lOa-pregnene 5 1. 3 fl-tetrahydropyranyloxy-ZO-cycloethylenedioxy- 19-vinyl-16,8-methyl-A -lOar-pregnene 52. 3fl-tetrahydropyranyloxy-20-cycloethylenedioxy- 19-vinyl-16a,l7a-isopropylidenedioXy-A -10o:- pregnene 5 3. 3 8,17a-bis-tetrahydropyranyloxy-2O-cycloethylenedioxy-19-vinyl-A -10ot-pregnene 54. 3/3,17wbis-tetrahydropyranyloxy-20-cycloethylenedioxy-19-vinyl-l6 a-methyl-A L- pregnene Example X To a solution of 1 g. of compound No. 7 in 30 cc. of acetic acid was added 0.5 cc. of 2 N hydrochloric acid. After 1 hour at room temperature, ice water was added and the product extracted withimethylene chloride. The extract was washed to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetonehexane yielded l9-formyl-A -l0u-pregnen- 3fl-ol-20-one (Cpd. No. 55).

The compounds Nos. 8 to 54, inclusive, were treated following the same procedure, thus giving, respectively, the following compounds:

Cpd. No.:

- 5 6. l9-formyl-16u-methyl-A -l0a-pregnen-3p-ol-20- one 57. 19-formyl-16B-methyl-A -l0a-pregnen-3fl-ol-20- one 58. 19-formyl-16a,17oc-isopropylidenedioxy-A -10apregnen-BB-ol-ZO-one 59. 19-formyl-A -10a-pregnene-3fl,17a-diol-20-one 60. 19-formyle16wmethyl-A -1Oa-pregnene-3 5,170-

diol-20-one 61. 19-hydroxymethyl-A 1 Ou-pregnen-S B-ol-ZO-one 62. 19-hydroxymethyl-16a-methyl-A 10a-pregnen- 3,8-ol-20-one 63. 19-hydroxymethyl-16p-methyl-A -IOa-pregnen- 3,8-01-20-one 64. 19-hydroxymethyl-16u,17a-isopropylidenedioxy- A -1Oa-pregnen-3l3-ol-2O-one 65. 19-hydroxymethyl-A 10a-pregnene-3/3,17u-diol- 20-one 66. l9-hydroxymethyl-16a-methyl-A -IOu-pregnene- 35,17a-di0l-20-one 67. 19-tosyloxymethyl-A -lOu-pregnen-3B-ol-20-one 68. 19-tosyloxymethyl-16u-rnethyl-A dOaregnen- 3B-ol-20-one 69. 19-tosyloxyme'thyl-165-methyl-A -10a-pregnen- 3fl-ol-20-one 70. 19-tosyloxymethyl-161x,17a-isopropylidenedioxy- A IOa-pregnen-BB-ol-ZO-one 71. 19-tosyloxymethyl-A 1 Oa-pIegnene-B'fi, l 706-dl0l- 20-0ne 72. 19tosyloxymethyl-16ot-methyl-A -lOu-pregnene- 3B,17a-diol-20-one 73 19-fluoromethyl-A 1 0m-pregnen-3 3-01-20-one 74. 19-fiuoromethyl-16zx-methyl-A -10a-pregnen- 3,8-ol-20-one 75. 19'-fiuor0methyl-16B-methyl-A -lOwpregnen- 3B-ol-20-one 76. 19-fluoromethyl-l6a,l7a-isopropylidenedioxy- A -10a-pregnen-3p-ol-20-one 77. 19-fiu0romethyl-A -10a-pregnene-3B,l7a-diol- 20-or1e dium carbonate solution and water.

15 Cpd. No.Continued 150. 19-vinyl-IGa-methyl-AH0e-pregnen-l7a-ol- 3,20-dione Example XII A mixture of 1 g. of compound No. 55, 4 cc. of pyridine and 2 cc. of acetic anhydride was kept at room temperature overnight, poured into ice water, the formed precipitate was filtered, washed with water and dried. Crystallization from acetone-hexane gave 19-formy1-A -10upregnen-3B-ol-20-one acetate (Cpd.,No. 151).

The compounds Nos. 59, 62, 65, 70, 73, 83, 91 and 97,

were treated by the same procedure, thus giving respec-.

tively:

The starting compounds of Example XII. were treated following exactly the procedure described in that example,

except that acetic arihydride was substituted by caproic.

anhydride, propionic anhydride, enanthic anhydride and cyclopentylpropionic anhydride, thus affording respectively the. corresponding caproates, propionates, enanthates and cyclopentylpropion ates. of said starting compounds.

Example XIV To a solution of 5 g. of compound No. 59 in 100 cc. of anhydrous benzene there were added 1 g. of p-toluenesulfonic acid and 10 cc. of caproic anhydride and the mixture was allowed to stand for 24 hours at room temperature, poured into ice and water, and the resulting mixture stirred to elfect hydrolysis of the excess anhyd-ride. The benzene layer was separated and washed with 10% so- Drying, evaporation and crystallization of the residue from ether-hexane produced 19-formyl-A -1Oa-pregnene-3B,17a-diol-2O-one dicaproate (Cpd. N0. 160).

The compounds Nos. 65, 72, 77, 84, 95, 102, 152, 154, and 157 were treated by the same procedure, thus yeildmg respectively:

Cpd. No.:

161. 19-caproxymethyl-A -1Oa-pregnene-3fi,l7udiol-20-one dicaproate 162. 19-tosyloxymethyl-16a-methyl-A -la-pregnene-3,8-,17a-diol-20-one dicaproate 163. 19-fluoromethyl-A -1Oa-pregnene-3fl-17wdiol- 20-one dicaproate 164. 19-chloromethyl-16a-methyl-A -IOaregnene- 35,17oe-di0l-20-0ne dicaproate 165. 19-cyanomethyl-A -IOu-pregnene-SB,l7a-diol- 20-one dicaproate 166. 19-vinyl-16a-methyl-A -1Oa-pregnene-3fi,17m-

diol-ZO-one dicaproate 167. 19-formyl-A 1 0a-pregnene-3 8, 17a-diol- 20-one 3-acetate-17-caproate 1'68. l9-acetoxymethyl-A -1()u-pregnene-3fl,l7u-diol- 20-one 3-acetate-l7-caproate 169. 19-chloromethyl-A -10a-pregnene-3,B,17u-diol- 20-one 3-acetate-17-caproate.

16 Cpid. No.Oon-tinued The compounds Nos. 107,108, 113, 114, 125, 132, 143, and 149, were treated following exactly the same procedure, to give respectively:

Cpd. No.:

170. l9-formyl-A -l0e-pregnen-l7a-ol-3,20-dione caproate 171. 19-formyl-l 6a-methy1-A 1 Oa-pregnen- 1 7a-ol- 3,20-dione caproate 172. l9-caproxymethyl-A l Oaregnenl 7cc-Ol-3 ,20-

dione caproate 173. l9-caproxymethyl- 1 6a-methyl-A 1 Ou-pregnenl7u-ol-2,30'-dione caproate 174. l9-fluoromethyl-A -lOu-pregnen-17oa-ol-3,20-

dione caproate 175. 19-chloromethyl-l6e-methyl-A -IOa-pregnen- 17a-ol-3,20-dione caproate 176. 19-cyanomethyl-A -10a-pregnen-17a-ol-3,20-

dione caproate- 177. 19-vinyl-A -lOu-pregnen-l7a-ol-3,20-dione caproate Example XV The starting compounds of Example XIV were treated following exactly the procedure described in that example,

except that caproic anhydride was substituted by ace-tic anhydride, propionic anhydride, euanthic anhydride and cyclopentylpropionic anhydride, thus afiording respectively the corresponding acetates, propionates, enanthates, and cyclopentylpropiona-tes of said starting compounds.

Example XVI A-cooled solution of 4 g. of compound No. 107 in cc. of tetrahydrofuran and 18 cc; of methanol wastreated under continuous stirring with 6 g. of pure calcium oxide, in small portions, and then with6 g. of iodine. The

stirring was continued at room temperature until the solution turned pale yellow. The mixture was poured into ice water containing 18 cc. of acetic acid and 2 g. of sodium triosulfate. After stirring for 15 minutes the solution was decanted and the precipitate was collected by filtration, thus giving 2l-iodo-19-formyl-16u,17u-isopropylidene dioxy-A -l0a-pregnene-3,ZO-dione (Cpd. No. 178). This compound was mixed with cc. of acetone and 12 g. of recently fused potassium acetate and the mixture was refluxed for 8 hours, concentrated to a small volume, diluted with water and extracted with ethyl acetate; the extract was washed with water, dried over anhydrous sodium sulfate and concentrated until crystallization started. The precipitate was collected and crystallized from methanolwater, thus yielding 19-formyl-16a,17a-isopropylidenedioxy-A -l0wpregnen-21-ol-3,20-dione acetate (Cpd. No. 179).

The following solutions A, B and C were prepared using distilled water as solvent: solution A was prepared by mixing 425 cc. of a 1.742% dipotassic phosphate solution (K HPO with 75 cc. of 1.38% monosodic phosphate; solution B was prepared by diluting a mixture of 1 It. of 4.5% sodium chloride solution, 40 cc; of a 5.75% potassium chloride solution and 10 cc. of a 19.1% magnesium sulfate, to a volume of 5 lt.; solution C was prepared by dissolving 20.9 -g. of fumaric acid and 14.4 g.-of.sodium hydroxide in 1 lt. of water and diluting the solution to 1.2 lt.' Then 475 cc. of solution A, 4.32 It. of solution B and 1.2 lt. of solution C .were mixed.

The acetone extract was separated by filtration, the ground adrenals were washed with 6 liters of ace-tone, the

extracts were combined and the solvent removed by dis- Cpd. No.:

181. 19 formyl A -10 t-pregnene-115,17a-21-triol- 3,20-dione 182. 19 formyl 16 methyl-A -10a-pregnene- 11 13, 1721:,21-i110l-L2O-dl0116 183. 19 hydr0xymethyl-16u,l7atisopropyl.idenedioxy-A l 0a-pregnene-l 1,8,2 l-diol-3 ,20-dione 184. 19 hydroxymethyl A -10a-pregnene-118,1701,-

21Ftriol-3,20-dione 185. 19 hydrox-yrnethyl l6u-Inethyl-A -I'M-pregnene-l 15,170:,2141101-120-(110116 186. 19 fluorornethyl 16a,l7u-isopropylienedioxy- A -a-pregnene-l 1 ,B,21-diol-3,20-dione 1 87. 19 fluoromethyl A -10ot-pregnene-1lfi,l7a,2l-

triol-3,20-dione 189.19 chloromethyl 16a,17ot-isopropylidenedioxy-A IOu-pregnene-l 16,21-diol-3 ,20-dione 190. 19 chlorometh-yl A -10m-pre-gnene-11,6,17a,2l-

triol-3, -dione 191. 19 chloromethyl 16ot-rnethyl-A -l0apreg nene-l1 8,l7a,2l-triol-3,20-dione 192. 19 bromomethyl 16a,l7a-isopropylidenedioxy-A -10ot-pregnene-l 1B,Z1-diol-3,20-,dione 193. 19 bromomethyl-A IOQt-pregnene-I1B,17a,21-

triol-3,20dione 194. 1'9 bromomethyl-l6a-1nethyl-A -1Goa-pregnenel 1B,17u,2l-triol-3,20-dione 195. 19 cyanomethyl-16a,17ot-isopropylidenedioxy- A .-1'Ou-pregnene-1 1,8,21-diol-3 ,20-dione 196. 19 cyanometh-yl-M-lfla-pregnene-l'lfl,1711,21-

trio'l-3,20-dione 197. 19' cyanomethyl-16a-methyl-A -10u-pregnene- 1'1;3,17a,2l-triol-3,20-dione I 198. 19 vinyl-16a,17u-isopropylidenedioxy-A -10epregnene-l1,6,21-diol-3,20-dione '199. 19 viny1-A -1 0u-pregnene-11fi,17u,21-triol-3,

20-dione 200. 19 vinyl 16u-methyl-A -lOa-pregnene-l1,8,-

17a,21-triol-3,20-dione.

Example VII A mixture of 10 g. of compound No. 180, 410 cc. of pyridine and 20 cc. of acetic anhydride was kept at room temperature overnight, poured into ice water, the formed precipitate was filtered, washed with water and dried. Crystallization from acetone-hexane gave 19-forrnyl-1 6a; 17cc isopropylidenedioxy M-lOa-pregnene-l15,21-dio1- 3,20-dio11e 2l-acetate (Cpd. No. 201).

,9 g. of compound No. 201 was dissolved with slow heating in 125 cc. of dimethylformamide, the mixture was cooled, 4.5 g. of mesyl chloride and 5 cc. of pyridine were added and the solution was kept at 80 C. for half an hour. The reaction mixture was cooled, water was added and the product was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated. Recrystallization of the residue from acetone-hexane furnished 19 formyl 16a,17otisopropylidenedioxy-A -10mpregnadien-Z1-ol-3,20-dione acetate (Cpd. No. 202).

2.8 g. of N-bromoacetamide were added to a mixture of 5 g. of compound No. 202, 50 cc. of pure dioxane and 0.8 cc. of 0.4 N perchloric acid while stirring in the dark and at room temperature during 1 hour. The reaction mixture was stirred for 1 hour further, a solution of 10% sodium sulfite was then added until the potassiumstarch indicator paper no longer turned blue, ice was added, the mixture was extracted with chloroform and the extract was washed consecutively with Water, 5% aqueous sodium bicarbonate solution and water, and the solvent was removedby distillation under vacuo. By trituration of the residue with acetone there was obtained c bromo 19-formyl-l6a,17a-isopropylidenedioxy-A IOu-pregnene-Ilfi,2l-diol-3,20-dione 21-acetate (Cpd. No. 203).

A mixture of 2 g. of anhydrous potassium acetate and 20 cc, of acetone was heated almost to boiling and then a solution of 1.7 g. of the latter bromohydrin in 20 c. of acetone was added slowly while stirring; the mixture was then refluxed for- 10 hours, cooled and almost all of the acetone was distilled off; iced-Water was then added,

the precipitate was filtered, washed with water and dried.

at a temperature lower than 10 C. for 6 additional hours,

then neutralized by cautiously adding a 5% aqueous sodium bicarbonate solution and transferred to a separatory funnel. The organic layer was washed with :water, dried over anhydrous sodium sulfate and concentrated until formation of an abundant precipitate. The mixture was cooled, the precipitate filtered and redissolved in hot ethyl acetate, the insoluble material was filtered off and the filtrate cooled whereby there crystallized 9u-fluoro-l9- formyl 16a,17a isopropylidenedioxy-M-lOu-pregnene- 1l/3,21-diol-3,20-dione 2l-acetate (Cpd. No. 205).

The compounds Nos. 181 to 200, inclusive, were treated by the same sequence of reactions thus affording firstly the correspdoning acetates of the primary alcohols, secondly the corresponding A -acetates, thirdly the corresponding 90c bromo 11/3 hydroxy derivatives, fourthly the corresponding 9B,11/3 oxido compounds, and finally, respectively, the following compounds:

Cpd. No.:

206. 9a-fluoro-19-forrnyl-A -IOa-pregene- 1 1 {3,17 a,21t1'10l-3,20di0116 21-acetate 207. 906-11110110- 1 9-formyll 6a-methyl-A 1 0apregnene-l1fl,17u,2l-triol-3 ,20-dione 21-acetate 208. 9m-fluoro-19-acetoxymethyl-l6a,17a-isopropylidenedioxy-A- l0a-pregnene- 1 113,2 l-diol-3,20- dione 2l-acetate 209. 9u-fluoro-l9-acetoxymethyl-A -IOa-pregnene- 11B,17a,21-triol-3,20-dione 2 l-acetate 210. 9a-fluoro-l9-acetoxymethyl-16aamethyl A a 10oc-pregnene-l1fi,l7oc,21-triol-3,20-dione 21- acetate 211. 9or-fluoro-l9-fiuoromethyl-l6a,17a-isopropylidenedioxy-A -1Oa-pregnene-l lfi,21-diol-3,2.0-dione 21-acetate 213. 9wfluoro-l9-fluoromethyl-16a-methyl-A -10apregnene-l1,6,17a,2l-triol-3,20-dione 21-acetate 214. 9ot-fluoro-l9-chloromethyl-16a, 17 a-isopropylidenedioxy-A -lOu-pregnene-l 1,8,21-diol-3 ,20-dione 2 l-acetate Cpd. No.Co-ntinued 215. 9u-fluoro-9-chloromethyl-A -IOa-pregnene- 11B,17a,21-triol-3,20-dione 2 l-acetate 216. 9a-fluoro-19-chloromethyl-16a-methyl-A -10apregnene-l1,8,17a,21-triol-3,20-dione 21-acetate 217. 9a-fluoro-19-bromomethyl-l6u,17a-isopropylidenedioxy-A -1Oa-pregnene-I 1,8,21-diol-3,20- dione 21-acetate 218. 9a-fluoro-l9-bromomethyl-A -lOa-pregnene- 11fl,17u,21-triol-3,20-dione 2l-acetate 219. 9a-fluoro-l9-bromomethyl-16a-methyl-A -lapregnene-l1,8,17u,21--trio1-3,20-dione ZI-acetate 220. 9ot-fiuoro-19-cyanomethyl-16a,17a-isopropylidenedioxy-M-IOa-pregnene-I1,8,21-dio1-3 ,20- dione 21acetate 221. 9a-fluoro-19-cyanomethyl-A -IOa-pregnene- 11/3,l7u,2l-triol-3,20-dione 21-acetate 222. 9ot-fluoro-19-cyanomethyl-16a-methylA -u pregnene-l1,8,17a,21-triol-3 ,20-dione 21-acetate 223. 9a-fluoro-19-vinyl-16a,17a-isopropylidenedi0xy-A -10a-pregnene-11fi,21-diol-3,20 dione 21-acetate v 224. 9a-fluoro-19-vinyl-A -lOzx-pregnene-l1B,17a,21-

triol-3,20-dione 21-acetate 225. 9oc fiuoro-19-vinyl-l6tx-methyl-A -lOu-pregnene- 11,8,17a,21-triol-3,20-dione 21-acetate.

Example XVIII To a solution of 4 g. of compound No. 204 in 40 cc. of anhydrous chloroform, was added, over a period of 35 minutes, 30 cc. of a 0.45 N solution of dry hydrogen chloride in chloroform, under continuous stirring and maintaining the temperature around 0 C. The mixture was then stirred at 0 C. for 1 hour further, diluted with water and the chloroform layer was separated, washed with aqueous sodium bicarbonate solution and then with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. Crystallization of the residue from acetone-hexane gave 9oc-chloro-l9-formyl- 160t,17oc isopropylidenedioxy A 10a pregnene- 1l/8,21-diol-3,20-dione 2l-acetate (Cpd. No. 226).

The rest of the 95,11fi-oxido compounds obtained according to Example XVII were treated by the latter procedure, to give:

Cpd. No.:

227. 19-chl0ro-19-formyl-A -lOa-pregnene- 11/3,17a,21-triol-3,20-dione 21-acetate 228. 19-chloro-19-formyl-16a-methyl-A -10ocpregnene-l1;8,17ot,21-triol-3 ,20-dione 2l-acetate 229. 19-chloro-19-acetoxyrnethyl-16a,17ot-isopropylidenedioxy-M- 1 Oa-pregnene-l 1,8,21-diol-3,20- dione 21-acetate 230. 19-chloro-19-acetoxymethyl-A -IOa-pregnene- 11B,17u,21-triol-3,20-dione 21-acetate 23 1. 19-chloro-19-acetoxymethyl-16a-rnethyl-A 10a-pregnene-11,8,17a,21-triol-3,20-dione 21- acetate 232. 19-chloro-19-fluoromethyl-16a,17a-isopropylidenedioxy-A 1 Oa-pregnene-l 1,8,2 l-diol-3 ,20- dione 21-acetate 233. 19-chloro-19-fiuoromethyl-A -IOa-pregnene- 11 8,17a,21-tri0l-3,20-dione ZI-acetate 234. 19-chloro-19-fluoromethyl-16ot-methyl-A 1 [)ocpregnene-l1,8,l7u,2l-triol-3,20-dione 21-acetate 235. 19-chloro-19-chloromethyl-16a,17u-isopropylidenedioxy-M-IOa-pregntme-l1 8,21-diol-3,20- dione 21-acetate 236. 19-chloro-19-chloromethyl-A -1Oa-pregnene- 11,8,17a,21-trio1-3,20-dione 21-acetate 237. 19-chloro-19-chloromethyl-l6ot-rnethyl-A -10apregnene-l1fl,17a-triol-3,20-dione 21-acetate 238. 19-chloro-19-bromomethyl-16u,17oz-isopropy1- idenedioxy-A I'Oa-pregnene-l 1fi,21-diol-3,20- dione 21-acetate 20 Cpd. No.Conitinued 239. 19-chloro-19-bromomethyl-A IOa-pregnene- 1113,17a,2l-triol-3,20-di0ne 21-acetate 240. 19-chloro-l9-bromomethyl-16a-methyl-A -10w pregnene-l 1p,17a,21-triol-3,20-dione 21-acetate 241. v19-chloro-19-cyanomethyl-16r,17o-isopropylidenedioxy-A IOa-pregnene-l 113,2 1-diol-3,20- dione 21-acetate 242. 19-chloro-19-cyanornethyl-A -IOa-pregnene- 11B,17a,21-triol-3,20-dione 21-acetate 243. l9-chlo'ro-19-cyanomethyl-16ot-methyl-A -l0apregnene-l1,8,17a,21-triol-3,20-dione 21-acetate 244; 19-chloro-19-vinyl-16a,17a-isopropylidenedioxy-A -10ot-pregnene-1 15,2 1-diol-3,20-dione 21- acetate 245. 19-chloro-19-vinyl A -1Oa-pregnene-l1153170421- triol-3,20-dione 21-acetate- 246. 19-chloro-19-vinyl-16a-methy1-A -10a-pregnene-l1B,17a,21-triol-3,20-dione 21-acetate Example XIX A solution of 1 g. of compound No. 201 in 10 cc. of acetone was cooled to 0 C. and treated under an atmosphere of nitrogen and with stirring, with a solution of 8 N chromic acid (prepared by mixing 26 g. of chromium trioxide with 23 cc. of concentrated sulfuric acid and diluting with water to cc.), until the color of the reagent persisted in the mixture. It was stirred for 5 minutes further at 05 C. and diluted with water. The precipitate was collected, washed with water and dried under vacuum, thus affording a crude product which upon recrystallization from acetone-hexane gave 19- formyl 16a,17a-isopropylidenedioxy-A -10a-pregnen-21- ol-3,11,20-trione acetate (Cpd. No. 247).

The rest of the 11(3-hydroxy-21-acetates obtained according to Example XVIIwere treated by the same procedure, thus giving the corresponding 11-keto-21- acetates.

The compounds'Nos. 226 to 246, inclusive, were treated by the latter procedure, thus alfo rding the corresponding ll-ketones.

Example XX The compound No. 247 was treated according to Example XX, thus yielding 19-fOI myl-16oc,17oc-iSOp1'OPYlidene-dioxy-A -IOoc-pregnen 21-ol-3,11,20-trione (Cpd. No. 249).

The rest of the compounds obtained in accordance with Example XIX were treated by the same procedure thus atfording the corresponding free alcohols.

Example XXII A mixture of 10 g. of compound No. 248, 40 cc. of

pyridine and 20 cc. of caproic anhydride was kept at room temperature overnight, poured into ice water, the formed precipitate was filtered, washed with water and dried. Crystallization from. acetone-hexane gave 9oz-fiI1OIO-l9- formyl-16a,17a-isopropylidenedioxy A -IOwpre'gnene-I1,8,.

21-diol-3,20-dione 2l-caproate (Cpd. No. 250).

The rest of the compounds obtained according to example XX and all the compounds obtained accordingto Example XXI were treated by the same procedure, thus giving the corresponding caproates.

The formed precipitate was collected 21 Example XXIII The starting compounds of Example XXII were treated following exactly the procedure described in that Example, except that caproic anhydride was substituted by I propionic anhydride, enanthic anhydride and cyclo pentylpropionic anhydride, thus affording respectively the corresponding propionates, enanthates, and cyclopentylpropionates of said starting compounds.

I claim:

1. A compound of the following formula:

r RQCH if; t U" i rt o wherein R is selected from the group consisting of hydroxyl, tosyloxy, a hydrocarbon carboxylic acyloxy group of less than 13 carbon atoms and a cyano group; R is hydrogen; R and R taken together are selected from the group consisting of an oxo group and a methylene grouping; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is a member of the group consisting of hydrogen, hydroxyl and a hyrocarbon carboxylic acyloxy group of less than 12 carbon atoms; T is selected from the group consisting of hydrogen and methyl; and R and T,

together, form a 16m, I7a-YIOW'QI a-lkylidenedioxy grouping.

2. A compound of the following formula:

wherein R is selected from the group consisting of hy: droxyl, tosyloxy, a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms and a cyano group; R is hydrogen; R and R taken together are methylene; R is a member of the group consisting of hydrogen, hydroxyl and a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms; T is selected from the group 22 consisting of hydrogen and methyl; and R and T, ,together, form a l6a,17a-lower alklidenedioxy grouping.

4. A compound of the following formula:

=0 X m t U (511 wherein R is selected from the group consisting of hydroxyl, a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms and a cyano group; R is hydrogen; R and R taken together are methylene; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R

is hydrogen; T is selected from the group consisting of hydrogen and methyl; OR and T, together, form a 160:, 17oc-10W6I alkylidenedioxy grouping; and Y is selected from the group consisting of hydrogen and a halogen atom having an atomic weight of less than Z is a member of the group consisting of ,B-hydroxyl and an oxo group.

6. A compound of the following formula:

wherein X is a halogen atom having an atomic weight of less than 125; Y is selected from the group consisting of hydrogen and a halogen atom having an atomic weight of less than 125; Z is a member of the group consisting of ,B-hydroxyl and an oxo group; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is hydrogen; T is selected from the group consisting of hydrogen and methyl; and CR and T, together, form a 17cc-1OW6I alkylidenedioxy grouping.

7. 19-formyl-A 1Oa-pregnen 3B-ol-20-one.

8. 19 formyl 16a methyl A 10a pregnen 3 3 ol-20-one.

9, l9 formyl 16B methyl A 7 10oz pregnen 3,8 ol-20-one.

10. 19-formyl 16a,l7a-isopropylidenedioxy A 40- pregnen-3B-ol-20-one. 

1. A COMPOUND OF THE FOLLOWING FORMULA: 